In this study we analyzed a knock-in (KI) mouse strain engineered to harbor a point mutation in the Nlrp3 gene encoding NLRP3 equivalent to that in patients with Muckle-Wells Syndrome. The KI mice exhibited increased NLRP3 inflammasome activity characterized by ATP-independent IL-1beta as well as IL-18 secretion and developed dermatitis as do patients with this autoinflammatory disorder. Importantly, the spontaneous and contactant-induced skin inflammation was characterized by a cytokine response strongly skewed to Th17 cytokines that was mediated at least in part by dysregulated antigen-presenting cells producing IL-1beta. This conclusion was highlighted by the fact that administration of either anti-IL-1R or anti-IL-17A led to marked resolution of the skin inflammation. The robust IL-17 responses characterizing inflammasome inflammation are likely to contribute to the neutrophilic infiltration characterizing this inflammation as well as its intensification via neutrophil production of IL-1beta. While the NLRP3 inflammasome of antigen-presenting cells (APCs) from knock-in (KI) mice was hyperactive it still required TLR stimulation for activation. Nevertheless, NLRP3 activation was more easily triggered in the KI cells than in normal cells because it could occur in the absence of exogenous ATP, a molecular that is ordinarily necessary for the cell membrane pore formation through which TLR ligands can gain entry into the cell. We found that such ATP-independent activation was not due to abnormalities of ligand entry into knock-in cells, but rather due to a lowered threshold for activation, whereby the inflammasome is triggered by low concentrations of ligand in the absence of exogenous ATP. This conforms to a model in which the inflammasome contains a mutated NLRP3 that is more easily activated because of a protein conformational change resulting from the mutation. Parenthetically, it is important to mention that the NLRP3 inflammasome is triggered by a broad number of TLR ligands and other substances such as uric acid. Thus, it is likely that the recognition unit of the inflammasome (the LRR domain of NLRP3) is responding to a common intra-cellular molecule activated by such stimulants rather than to the original stimulus. The lower threshold of NLRP3 activation in the KI mice could explain the fact that they were susceptible to spontaneous skin inflammation, since the latter was most likely triggered by local trauma and exposure of cells to low concentrations of TLR ligands that are sufficient to activate the inflammasome of KI mice but not of normal mice. Inflammasome activation and resultant IL-1beta/IL-18 secretion may then lead to continued inflammasome activation by the production of endogenous inflammasome stimulants. As evidenced by the fact that Nlrp3 knock-in bone marrow transfer to Wt recipient mice resulted in the development of skin inflammation in recipient mice, we can conclude that the spontaneous skin inflammation that develop in KI mice was largely due to abnormalities in cells derived from the hematopoietic system. However, while NLRP3 is predominantly expressed in APCs such as macrophages and dendritic cells, it is also expressed in other cells including keratinocytes. It is thus possible that the skin inflammation observed in KI mice was also due, in part, to release of inflammasome related cytokines from keratinocytes. An important outcome of this study was the observation that in both spontaneous and contactant induced skin inflammation, knock-in mice exhibited Th17-predominant cytokine profiles in affected skin as well as lymphoid tissues. In extensive in vitro co-culture studies to determine the basis of this pprofile we established that the abnormality lies in the antigen presenting cell rather than in the T cell. In addition, the co-culture experiments revealed that the skewing could at least in part be attributed to the excess production of IL-1beta, in accordance with previous work on the properties of this cytokine. It should be noted, however, that in studies of human cells, augmentation for IL-17 production by IL-1beta alone or in association with IL-23 was seen in relation to the differentiation of memory T cells, but not in nave T cells which were the major cell population studied here. In addition, in studies of murine cells, IL-1beta appeared to be playing a role as a substitute for IL-6, or needed IL-23 to induce IL-17 expression, whereas in the present study only TGF-beta and IL-6 incubation were necessary antecedents to the effect of IL-1beta on Th17 differentiation. This suggests that in this context the IL-1beta was acting like IL-23, since it is now known that the major role of IL-23 is to sustain already differentiated IL-17 secreting cells rather than to induce these Th17 cells. These studies therefore indicate that IL-1beta plays an hitherto unexpected role in Th17 differentiation that will require further studies at the molecular level to fully understand. In both the tissue inflammation and co-culture studies, the enhancement of Th17 responses by APCs derived IL-1? was largely accompanied by decreased IFN-beta production. A possible explanation of this finding derives from previous work showing that IL-1? selectively inhibits IL-6 activated STAT-1 phosphorylation and thereby regulates T-bet transcription, the latter a key factor in Th1 differentiation. A second explanation derives from our observation that lesional tissue of KI mice exhibited down regulation of the IL-12Rb2 chain and that treatment of mice with anti-IL-1R1 reversed this effect. It is thus possible that while inflammasome activation may lead to secondary induction of IL-12p70 and other pro-inflammatory cytokines (as was indeed observed in lesional tissue) such IL-12p70 cannot induce IFNbeta production. On a related point, while lymph node and splenic CD4+ T cells from inflammed KI mice also manifested a Th17 skewing, the skewing in this case was rather modest and the cells also produced increased amounts of IFN-? and IL-4 compared with control cells. We attribute this global increase in cytokine production to the fact that these peripheral cells were exposed to a mixed cytokine microenvironment, consisting not only of IL-1? but also other cytokines such as IL-18 and IL-33, the latter two being involved in stimulating production of IFNgamma and IL-4 from naive T cells respectively.